HIV-1 infection and methamphetamine (METH) have devastating effects on the central nervous system (CMS). Moreover, drug abuse is very often associated with HIV-1 infection as a consequence of needle sharing. Treatment of these patients is a very complex process because it has to target two entities which are quite different in nature. Despite substantive research efforts, the mechanisms underlying cognitive impairment resulting from HIV-1 infection or METH use are far from understood. We posit that advances in proteomic techniques could lead to new markers of disease and critical insights into disease processes. We hypothesize that the protein composition of plasma samples contains unique proteomic signatures (fingerprints). Profiling of such samples from patients who stopped using METH will lead to identification and better understanding of molecular mechanisms underlying reversible (short-term) and non-reversible (long-term) effects of the interactions between HIV-1 infection and METH. The strengths of this proposal lie in its carefully selected and well defined cohort of clinical material, track record of a proven and successful use of innovative and technologically advanced "cutting edge" proteomic approaches, the interdisciplinary group of investigators, the prior development of proteomics-based biomarker discovery and functional proteomics platforms, the exclusive use of needed "cutting edge" equipment, and strong research and collaborative environment. Aim 1. To determine differences in proteome profiles of plasma which reflect short- and long-term withdrawal of METH. The work in this aim reflects the hypothesis that plasma contains in significant measure protein markers of HIV infection of CNS exposed to drug of abuse (METH), which could be used for better understanding of underlying molecular mechanisms. Aim 2. To substantiate the relevance of uncovered biomarkers in molecular mechanisms of the synergistic effect of HIV-1 infection and use of METH. The long-term goal of this aim is to validate iomarkers specific for concurrent effect of HIV and METH on the CNS which will be used for future, more 'focused and hypothesis driven projects. The public health relevance of this work relates to the overlapping populations of HIV infected people with those who use METH. Discovery of protein biomarkers in the blood will enable the study of the harmful effects of METH in the setting of HIV infection, leading to increased education efforts, improved diagnostics, and therapeutic inroads.